A subject of the present invention is new derivatives of 2-(iminomethyl)amino-phenyl which have an inhibitory activity on NO-synthase enzymes producing nitrogen monoxide NO and/or an activity which traps the reactive oxygen species (ROS). The invention relates to the derivatives corresponding to general formula (I) defined below, their preparation methods, the pharmaceutical preparations containing them and their use for therapeutic purposes, in particular their use as NO-synthase inhibitors and selective or non selective traps for reactive oxygen species.
Given the potential role of NO and the ROS""s in physiopathology, the new derivatives described corresponding to general formula (I) may produce beneficial or favourable effects in the treatment of pathologies where these chemical species are involved. In particular:
cardiovascular and cerebro-vascular disorders including for example atherosclerosis, migraine, arterial hypertension, septic shock, ischemic or hemorragic cardiac or cerebral infarctions, ischemias and thromboses.
disorders of the central or peripheral nervous system such as for example neurodegenerative diseases where there can in particular be mentioned cerebral infarctions, sub-arachnoid haemorrhaging, ageing, senile dementias including Alzheimer""s disease, Huntington""s chorea, Parkinson""s disease, Creutzfeld Jacob disease and prion diseases, amyotrophic lateral sclerosis but also pain, cerebral and bone marrow traumas, addiction to opiates, alcohol and addictive substances, erective and reproductive disorders, cognitive disorders, encephalopathies, encephalopathies of viral or toxic origin.
disorders of the skeletal muscle and neuromuscular joints (myopathy, myosis) as well as cutaneous diseases.
proliferative and inflammatory diseases such as for example atherosclerosis, pulmonary hypertension, respiratory distress, glomerulonephritis, portal hypertension, psoriasis, arthrosis and rheumatoid arthritis, fibroses, amyloidoses, inflammations of the gastro-intestinal system (colitis, Crohn""s disease) or of the pulmonary system and airways (asthma, sinusitis, rhinitis).
organ transplants.
auto-immune and viral diseases such as for example lupus, AIDS, parasitic and viral infections, diabetes, multiple sclerosis.
cancer.
neurological diseases associated with intoxications (Cadmium poisoning, inhalation of n-hexane, pesticides, herbicides), associated with treatments (radiotherapy) or disorders of genetic origin (Wilson""s disease).
all the pathologies characterized by an excessive production or dysfunction of NO and/or ROS""s.
In all these pathologies, there is experimental evidence demonstrating the involvement of NO or ROS""s (J. Med. Chem. (1995) 38, 4343-4362; Free Radic. Biol. Med. (1996) 20, 675-705; The Neuroscientist (1997) 3, 327-333).
Furthermore, NO Synthase inhibitors, their use and more recently the combination of these inhibitors with products having antioxidant or antiradicular properties have already been described in previous Patents (respectively U.S. Pat. No. 5,081,148; U.S. Pat. No. 5,360,925 and an unpublished Patent Application).
A subject of the present invention is the derivatives of 2-(iminomethyl)amino-phenyl, their preparation and their therapeutic use.
The compounds of the invention correspond to general formula (I): 
in which:
A represents:
xe2x80x83either a 
xe2x80x83radical in which R1 and R2 represent, independently, a hydrogen atom, a halogen, the OH group, a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms,
R3 represents a hydrogen atom, a linear or branched alkyl radical having from 1 to 6 carbon atoms or a xe2x80x94COR4 radical,
R4 represents a linear or branched alkyl radical having from 1 to 6 carbon atoms,
xe2x80x83or a 
xe2x80x83radical in which R3 has the meaning indicated above
xe2x80x83or a 
xe2x80x83radical in which R5 represents a hydrogen atom, the OH group or a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms;
B represents a linear or branched alkyl radical having from 1 to 6 carbon atoms, carbocyclic or heterocyclic aryl with 5 or 6 members containing from 1 to 4 heteroatoms chosen from O, S, N and in particular the thiophene, furan, pyrrole or thiazole radicals, the aryl radical being optionally substituted by one or more groups chosen from the linear or branched alkyl, alkenyl or alkoxy radicals having from 1 to 6 carbon atoms;
X represents xe2x80x94Z1xe2x80x94, xe2x80x94Z1xe2x80x94COxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94COxe2x80x94, xe2x80x94Z1xe2x80x94NR3xe2x80x94COxe2x80x94, xe2x80x94Z1xe2x80x94NR3xe2x80x94CSxe2x80x94, xe2x80x94Z1xe2x80x94NR3xe2x80x94SO2xe2x80x94 or a single bond;
Y represents a radical chosen from the xe2x80x94Z2xe2x80x94Q, piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethyl-piperazine, 4-aminopiperidine, xe2x80x94NR3xe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94NR3xe2x80x94COxe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94NR3xe2x80x94NHxe2x80x94COxe2x80x94Z2xe2x80x94, xe2x80x94NHxe2x80x94NHxe2x80x94Z2xe2x80x94, xe2x80x94NR3xe2x80x94Oxe2x80x94Z2xe2x80x94, xe2x80x94NR3xe2x80x94SO2xe2x80x94NR3xe2x80x94Z2xe2x80x94, xe2x80x94Oxe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94Z2xe2x80x94Qxe2x80x94 or xe2x80x94Sxe2x80x94Z2xe2x80x94Qxe2x80x94 radicals, in which Q represents a single bond, Oxe2x80x94Z3, R3xe2x80x94Nxe2x80x94Z3 or Sxe2x80x94Z3;
Z1, Z2 and Z3 represent independently a single bond or a linear or branched alkylene radical having from 1 to 6 carbon atoms; preferably, Z1, Z2 and Z3 represent xe2x80x94(CH2)mxe2x80x94, m being an integer comprised between 0 and 6;
R6 represents a hydrogen atom or an OH group;
or are salts of the latter.
The compounds of general formula (I) containing an asymmetrical centre are of isomeric form. The racemic and enantiomeric forms of these compounds also form part of this invention.
The compounds of the invention can exist in the state of bases or of addition salts in particular with organic or inorganic acids or with bases, and in particular in the state of hydrates, hydrochlorides, dihydrochlorides, fumarates or hemifumarates.
By linear or branched alkyl having from 1 to 6 carbon atoms is meant in particular the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexyl radicals. By linear or branched alkoxy having from 1 to 6 carbon atoms is meant radicals the alkyl radical of which has the meaning indicated previously.
By halogen is meant fluorine, chlorine, bromine or iodine atoms.
A particular subject of the invention is the following compounds of general formula (I), described in the examples (in the form of salts in certain cases):
3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[(2-thienyl (imino)methyl)amino]phenyl}-benzamide;
3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[[(2-thienyl (imino)methyl)amino]phenyl]methyl}-benzamide;
4-acetoxy-3,5-dimethoxy-N-{4-[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamide;
3,5-dimethoxy-4-hydroxy-N-{4-[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamide;
3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[2-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamide;
4-acetoxy-3,5-dimethoxy-N-{4-[2-[(2-thienyl-(imino)methyl)-amino]phenyl]ethyl}-benzamide;
3,5-dimethoxy-4-hydroxy-N-{4-[2-[(2-thienyl-(imino)methyl)-amino]phenyl]ethyl}-benzamide;
3,4,5-trihydroxy-N-{4-[2-[(2-thienyl(imino)methyl)-amino]phenyl]ethyl}-benzamide;
N-{4-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzoyl]-1-piperazinyl]-phenyl}-2-thiophenecarboximidamide;
N-{4-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzyl]-1-piperazinyl]phenyl}-2-thiophenecarboximdamide;
N-{4-[4-[3,5-dimethoxy-4-hydroxybenzoyl]-1-piperazinyl]-phenyl}-2-thiophenecarboximidamide;
3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-{4-[(2-thienyl (imino)methyl)amino]phenyl}-2H-1-benzopyran-2-carboxamide;
N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;
N-{4-[4-[(5-methoxy-1H-indol-3-yl)methylcarbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;
N-[4-[4-[{3-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-1-oxo-2-propenyl}-1-piperazinyl]-phenyl]]-2-thiophenecarboximidamide;
3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{3-[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamide;
N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-Nxe2x80x2-{{4-[(2-thienyl(imino)methyl)amino]phenyl}methyl}-urea;
N-[5-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl}amino]-2-hydroxyphenyl]-2-thiophenecarboximidamide;
N-[3-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl}-amino]-4-hydroxyphenyl]-2-thiophenecarboximidamide;
N-{4-[4-[3,4,5-trihydroxybenzoyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;
N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-Nxe2x80x2-{{4-[(2-thienyl(imino)methyl)amino]phenyl}carbonylamino}-urea;
N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-Nxe2x80x2-{{4-[(2-thienyl(imino)methyl)amino]phenyl}methyl}-thiourea;
N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-Nxe2x80x2-{2-{4-[(2-thienyl(imino)methyl)amino]phenyl}ethyl}-urea;
N-(4-{4-[(3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl}phenyl)-2-thiophenecarboximidamide;
N-[4-{4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1H-1,4-diazepin-1-yl}phenyl]-2-thiophenecarboximidamide;
(R)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;
(S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;
3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{2-[3-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamide;
N-{4-(4-[2-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-ethyl]-1-piperazinyl)phenyl}-2-thiophene-carboximidamide;
2-{4-[(2-thienyl(imino)methyl)amino]phenyl}ethyl 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-benzoate
2-{3-[(2-thienyl(imino)methyl)amino]phenyl}ethyl 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-benzoate
2-{2-[(2-thienyl(imino)methyl)amino]phenyl}ethyl 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-benzoate
as well as their salts, in particular their hydrochlorides, dihydrochlorides, fumarates or hemi-fumarates.
There will generally be preferred the compounds of general formula (I) for which:
X represents a linear or branched alkylene radical having from 1 to 6 carbon atoms and Y represents a piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine, 4-aminopiperidine, xe2x80x94NR3xe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94NR3xe2x80x94NHxe2x80x94COxe2x80x94Z2xe2x80x94, xe2x80x94NHxe2x80x94NHxe2x80x94Z2xe2x80x94 or xe2x80x94NR3xe2x80x94Oxe2x80x94Z2xe2x80x94 radical;
xe2x80x83or
X represents xe2x80x94Z1xe2x80x94COxe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94COxe2x80x94 and Y represents a piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine, 4-aminopiperidine, xe2x80x94NR3xe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94NR3xe2x80x94NHxe2x80x94COxe2x80x94Z2xe2x80x94, xe2x80x94NHxe2x80x94NHxe2x80x94Z2xe2x80x94, xe2x80x94NR3xe2x80x94Oxe2x80x94Z2xe2x80x94, xe2x80x94Oxe2x80x94Z2xe2x80x94Qxe2x80x94 radical or xe2x80x94NR3xe2x80x94COxe2x80x94Qxe2x80x2xe2x80x94 radical with Qxe2x80x2=R3xe2x80x94Nxe2x80x94Z3;
xe2x80x83or
X represents xe2x80x94Z1xe2x80x94NR3xe2x80x94COxe2x80x94 and Y represents xe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94NHxe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94NHxe2x80x94COxe2x80x94Z2xe2x80x94Qxe2x80x3xe2x80x94 with Qxe2x80x3=Oxe2x80x94Z3xe2x80x94, R3xe2x80x94Nxe2x80x94Z3xe2x80x94 or Sxe2x80x94Z3xe2x80x94, or Y represents xe2x80x94NR3xe2x80x94SO2xe2x80x94NR3xe2x80x94Z2xe2x80x94 or xe2x80x94Oxe2x80x94Z2xe2x80x94Qxe2x80x94;
xe2x80x83or
X represents xe2x80x94Z1xe2x80x94NHxe2x80x94COxe2x80x94 and Y represents a piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine, 4-aminopiperidine, xe2x80x94NR3xe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94NR3xe2x80x94NHxe2x80x94COxe2x80x94Z2xe2x80x94, xe2x80x94NHxe2x80x94NHxe2x80x94Z2xe2x80x94 or xe2x80x94NR3xe2x80x94Oxe2x80x94Z2xe2x80x94 radical;
xe2x80x83or
X represents xe2x80x94Z1xe2x80x94NR3xe2x80x94SO2xe2x80x94 and Y represents xe2x80x94Z2xe2x80x94Qxe2x80x3xe2x80x94 with Qxe2x80x3=Oxe2x80x94Z3xe2x80x94, R3xe2x80x94Nxe2x80x94Z3xe2x80x94 or Sxe2x80x94Z3xe2x80x94, or Y represents xe2x80x94NR3xe2x80x94Z2xe2x80x94Qxe2x80x94;
xe2x80x83or
X represents xe2x80x94Z1xe2x80x94 and Y represents xe2x80x94Oxe2x80x94COxe2x80x94Z2xe2x80x94Qxe2x80x94;
xe2x80x83or
X represents xe2x80x94Z1xe2x80x94NR3xe2x80x94CSxe2x80x94 and Y represents xe2x80x94NHxe2x80x94Z2xe2x80x94Qxe2x80x94, or a piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethyl-piperazine, 4-aminopiperidine, xe2x80x94NR3xe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94NHxe2x80x94NHxe2x80x94Z2xe2x80x94 or xe2x80x94NR3xe2x80x94Oxe2x80x94Z2xe2x80x94 radical;
xe2x80x83or
X represents a bond and Y represents xe2x80x94Oxe2x80x94Z2xe2x80x94NHxe2x80x94, xe2x80x94Sxe2x80x94Z2xe2x80x94NHxe2x80x94.
Moreover, the X-Y group will preferably be chosen from the following radicals: 
in which T represents a single bond, the xe2x80x94NR3xe2x80x94 radical or the xe2x80x94COxe2x80x94NR3xe2x80x94 radical, or 
in which Rp represents a hydrogen atom or a methyl radical, or 
in which U represents a xe2x80x94Z2, xe2x80x94NR3xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94Z2xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94NR3xe2x80x94 radical or an oxygen atom, or 
the Z1, Z2 and R3 radicals having the meaning indicated above.
In a preferential manner, the compounds according to the invention will be one of the following compounds:
3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[2-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamide;
3,4,5-trihydroxy-N-{4-[2-[(2-thienyl(imino)methyl)-amino]phenyl]ethyl}-benzamide;
N-{4-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzoyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;
N-{4-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;
3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-{4-[(2-thienyl (imino)methyl)amino]phenyl}-2H-1-benzopyran-2-carboxamide;
N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;
N-{4-[4-[(5 methoxy-1H-indol-3-yl)methylcarbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;
3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{3-[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamide;
N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-Nxe2x80x2-{{4-[(2-thienyl(imino)methyl)amino]phenyl}methyl}-urea;
N-[5-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl}-amino]-2-hydroxyphenyl]-2-thiophenecarboximidamide;
N-[3-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl}-amino]-4-hydroxyphenyl]-2-thiophenecarboximidamide;
N-{4-[4-[3,4,5-trihydroxybenzoyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;
N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-Nxe2x80x2-{{4-[(2-thienyl(imino)methyl)amino]phenyl}carbonylamino}-urea;
or a salt of one of the latter, in particular a hydrochloride, dihydrochloride, fumarate or hemi-fumarate of one of the latter.
Other preferred compounds for the invention will be the following compounds:
4-acetoxy-3,5-dimethoxy-N-{4-[2-[(2-thienyl-(imino)methyl)-amino]phenyl]ethyl}-benzamide;
3,5-dimethoxy-4-hydroxy-N-{4-[2-[(2-thienyl-(imino)methyl)-amino]phenyl]ethyl}-benzamide;
or a salt of one of the latter, in particular a hydrochloride, dihydrochloride, fumarate or hemi-fumarate of one of the latter.
Quite particularly preferred compounds of the invention will be as follows:
N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;
(R)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;
(S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;
or a salt of one of the latter, in particular a hydrochloride, dihydrochloride, fumarate or hemi-fumarate of one of the latter.
Finally, there will be particularly preferred for the invention the compounds of general formula (I) presenting the following characteristics:
either:
A represents: 
X represents xe2x80x94COxe2x80x94 or xe2x80x94NHxe2x80x94COxe2x80x94;
and Y represents an xe2x80x94NHxe2x80x94Z2xe2x80x94Qxe2x80x94 or piperazine radical, Q representing a single bond or an Oxe2x80x94Z3, R3xe2x80x94Nxe2x80x94Z3 or Sxe2x80x94Z3 radical, and Z2 and Z3 representing independently a bond or a linear or branched alkylene radical having from 1 to 6 carbon atoms and R3 represents a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms.
or: R6 is an OH group.
A subject of the invention is also, as medicaments, the compounds of general formula (I) described previously or their pharmaceutically acceptable salts. It also relates to pharmaceutical compositions containing these compounds or their pharmaceutically acceptable salts, and the use of these compounds or of their pharmaceutically acceptable salts for producing medicaments intended to inhibit neuronal NO synthase or inductible NO synthase, to inhibit lipidic peroxidation or to provide the double function of NO synthase inhibition and lipidic peroxidation.
By pharmaceutically acceptable salt is meant in particular addition salts of inorganic acids such as hydrochloride, sulphate, phosphate, diphosphate, hydrobromide and nitrate, or of organic acids, such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methane sulphonate, p-toluenesulphonate, pamoate, oxalate and stearate. The salts formed from bases such as sodium or potassium hydroxide also fall within the scope of the present invention, when they can be used. For other examples of pharmaceutically acceptable salts, reference can be made to xe2x80x9cPharmaceutical saltsxe2x80x9d, J. Pharm. Sci. 66:1 (1977).
The pharmaceutical composition can be in the form of a solid, for example powders, granules, tablets, capsules, liposomes or suppositories. Appropriate solid supports can be for example calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax.
The pharmaceutical compositions containing a compound of the invention can also be presented in the form of a liquid, for example, solutions, emulsions, suspensions or syrups. Appropriate liquid supports can be, for example, water, organic solvents such as glycerol or the glycols, as well as their mixtures, in varying proportions, in water.
A medicament according to the invention can be administered by topical, oral or parenteral route, by intramuscular injection, etc.
The envisaged administration dose for the medicament according to the invention is comprised between 0.1 mg and 10 g according to the type of active compound used.
The invention also offers, as new industrial products, the synthetic intermediates of the products of general formula (I), namely the products of general formula (II)A: 
in which:
W represents an amino or nitro radical,
A represents:
xe2x80x83either a 
xe2x80x83radical in which R1 and R2 represent, independently, a hydrogen atom, a halogen, the OH group, a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms,
R3 represents a hydrogen atom, a linear or branched alkyl radical having from 1 to 6 carbon atoms or a xe2x80x94COR4 radical,
R4 representing a linear or branched alkyl radical having from 1 to 6 carbon atoms,
xe2x80x83or a 
xe2x80x83radical in which R3 has the meaning indicated above or a 
xe2x80x83radical in which R5 represents a hydrogen atom, the OH group or a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms;
X represents xe2x80x94Z1xe2x80x94, xe2x80x94Z1xe2x80x94COxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94COxe2x80x94, xe2x80x94Z1xe2x80x94NR3xe2x80x94COxe2x80x94, xe2x80x94Z1xe2x80x94NR3xe2x80x94CSxe2x80x94, xe2x80x94Z1xe2x80x94NR3xe2x80x94SO2xe2x80x94 or a single bond;
Y represents a radical chosen from the xe2x80x94Z2xe2x80x94Q, piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine, 4-aminopiperidine, xe2x80x94NR3xe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94NR3xe2x80x94COxe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94NR3xe2x80x94NHxe2x80x94COxe2x80x94Z2xe2x80x94, xe2x80x94NHxe2x80x94NHxe2x80x94Z2xe2x80x94, xe2x80x94NR3xe2x80x94Oxe2x80x94Z2xe2x80x94, xe2x80x94NR3xe2x80x94SO2xe2x80x94NR3xe2x80x94Z2xe2x80x94, xe2x80x94Oxe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94Z2xe2x80x94Qxe2x80x94 or xe2x80x94Sxe2x80x94Z2xe2x80x94Qxe2x80x94 radicals, in which Q represents a single bond, Oxe2x80x94Z3, R3xe2x80x94Nxe2x80x94Z3 or Sxe2x80x94Z3;
Z1, Z2 and Z3 represent independently a single bond or a linear or branched alkylene radical having from 1 to 6 carbon atoms; preferably, Z1, Z2 and Z3 represent xe2x80x94(CH2)m, m being an integer comprised between 0 and 6;
R6 represents a hydrogen atom or an OH group;
with the exception however of 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-nitrophenyl)-benzamide;
or the salts of the latter.
Moreover, the invention offers in particular, as new industrial products, the following compounds, which are synthetic intermediates of products of general formula (I):
3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide;
3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide;
3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-aminophenyl)methyl]-benzamide;
4-acetoxy-3,5-dimethoxy-N-[(4-nitrophenyl)methyl]-benzamide;
4-acetoxy-3,5-dimethoxy-N-[(4-aminophenyl)methyl]-benzamide;
3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(4-nitrophenyl)ethyl]-benzamide;
3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(4-aminophenyl)ethyl]-benzamide;
4-acetoxy-3,5-dimethoxy-N-[2-(4-nitrophenyl)ethyl]-benzamide;
4-acetoxy-3,5-dimethoxy-N-[2-(4-aminophenyl)ethyl]-benzamide;
3,4,5-trihydroxy-N-[2-(4-nitrophenyl)ethyl]-benzamide;
3,4,5-trihydroxy-N-[2-(4-aminophenyl)ethyl]-benzamide;
2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-nitrophenyl)-1-piperazinyl]-carbonyl}-phenol;
2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-aminophenyl)-1-piperazinyl]-carbonyl}-phenol;
2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-nitrophenyl)-1-piperazinyl]-methyl}-phenol;
2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-aminophenyl)-1-piperazinyl]-methyl}-phenol;
2,6-dimethoxy-4-{[4-(4-nitrophenyl)-1-piperazinyl]carbonyl}-phenol;
2,6-dimethoxy-4-{[4-(4-aminophenyl)-1-piperazinyl]carbonyl}-phenol;
3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-(4-nitrophenyl)-2H-1-benzopyran-2-carboxamide;
3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-(4-aminophenyl)-2H-1-benzopyran-2-carboxamide;
3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-nitrophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol;
3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-aminophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol;
1-[(5 methoxy-1H-indol-3-yl)methylcarbonyl]-4-(4-nitrophenyl)-piperazine;
1-[(5 methoxy-1H-indol-3-yl)methylcarbonyl]-4-(4-aminophenyl)-piperazine;
2,6-bis-(1,1-dimethylethyl)-4-{3-[4-(4-nitrophenyl)-1-piperazinyl]-3-oxo-2-propenyl}-phenol;
2,6-bis-(1,1-dimethylethyl)-4-{3-[4-(4-aminophenyl)-1-piperazinyl]-3-oxo-2-propenyl}-phenol;
3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(3-nitrophenyl)methyl]-benzamide;
3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(3-aminophenyl)methyl]-benzamide;
N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-Nxe2x80x2-[(4-nitrophenyl)methyl]-urea;
N-[(4-aminophenyl)methyl]-Nxe2x80x2-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-urea;
3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(4-hydroxy-3-nitrophenyl)-2-propenamide;
3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(4-hydroxy-3-aminophenyl)-2-propenamide;
3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(2-hydroxy-5-nitrophenyl)-2-propenamide;
3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(2-hydroxy-5-aminophenyl)-2-propenamide;
5-{[4-(4-nitrophenyl)-1-piperazinyl]carbonyl}-benzene-1,2,3-triol;
5-{[4-(4-aminophenyl)-1-piperazinyl]carbonyl}-benzene-1,2,3-triol;
N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-Nxe2x80x2-[(4-nitrophenyl)-carbonylamino]-urea;
N-[(4-aminophenyl)carbonylamino]-Nxe2x80x2-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-urea;
N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-Nxe2x80x2-[(4-nitrophenyl)methyl]-thiourea;
N-[(4-aminophenyl)methyl]-Nxe2x80x2-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-thiourea;
N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-Nxe2x80x2-[2-(4-nitrophenyl)ethyl]-urea;
N-[2-(4-aminophenyl)ethyl]-Nxe2x80x2-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-urea;
1-{[3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl]carbonyl}-4-(4-nitrophenyl)piperazine;
1-{[3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl]carbonyl}-4-(4-aminophenyl)piperazine;
hexahydro-4-(4-nitrophenyl)-1H-1,4-diazepine;
1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]hexahydro-4-(4-nitrophenyl)-1H-1,4-diazepine;
1-(4-aminophenyl)-4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]hexahydro-1H-1,4-diazepine;
hydrochloride du N-[4-{4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1H-1,4-diazepin-1-yl}phenyl]-2-thiophenecarboximidamide hydrochloride;
(R)-3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-nitrophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol;
(R)-3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-aminophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol;
(S)-3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-nitrophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol;
(S)-3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-aminophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol;
3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(3-nitrophenyl)ethyl]-benzamide;
3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(3-aminophenyl)ethyl]-benzamide;
2-(4-nitrophenyl)ethyl 3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzoate;
2-(4-aminophenyl)ethyl 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-benzoate;
or their salts.
Finally, the invention offers processes for the preparation of compounds of general formula (I) as defined above and consisting, for example, of the reaction in a lower alcohol such as methanol, ethanol, isopropyl alcohol or t-butanol, preferably in isopropyl alcohol, at a temperature comprised between 20 and 90xc2x0 C., for example at 50xc2x0 C., and for 1 to 48 hours, preferably for 15 to 24 hours, optionally in the presence of DMF, of a compound of general formula (III) as defined above with a compound of general formula (IV) 
said compound of general formula (IV) being optionally salified by a mineral acid G, B having the meaning indicated above and L representing a leaving group and in particular an alkoxy, thioalkyl, sulphonic acid, halide, aryl alcohol or tosyl radical (other leaving groups well known to a person skilled in the art which can optionally be used for the invention are described in the following work: Advanced Organic Chemistry, J. March, 3rd Edition (1985), Mc Graw-Hill, p. 315). Preferably, G represents HCl, HBr or HI.
Other production processes can be envisaged and can be consulted in the literature (for example: The Chemistry of amidines and imidates, Vol. 2, Saul PATAI and Zvi RAPPOPORT, John Wiley and Sons, 1991).
According to the invention, the compounds of general formula (I) can be prepared by the process described below.
Preparation of Compounds of General Formula (I):
The compounds of general formula (I) can be prepared from intermediates of general formula (II) according to diagram 1.
The reduction of the nitro function of the intermediates of general formula (II) is generally carried out by catalytic hydrogenation in ethanol, in the presence of Pd/C, except when X=xe2x80x94CHxe2x95x90CHxe2x80x94COxe2x80x94 or Y=xe2x80x94Oxe2x80x94CH2xe2x80x94, the nitro group is selectively reduced using, for example, SnCl2 (J. Heterocyclic Chem. (1987), 24, 927-930; Tetrahedron Letters (1984), 25, (8), 839-842). The reaction is then carried out by heating the mixture to approx. 70xc2x0 C., for at least three hours, in ethyl acetate, sometimes with added ethanol.
The aniline derivatives of general formula (III) thus obtained can be condensed on derivatives of general formula (IV), for example derivatives of O-alkyl thioimidate or S-alkyl thioimidate type, in order to produce final compounds of general formula (I) (cf. diagram 1). For example, for B=thiophene, the derivatives of general formula (III) can be condensed on S-methylthiophene thiocarboxamide hydriodide, prepared according to a method in the literature (Ann. Chim. (1962), 7, 303-337). Condensation can be carried out by heating in an alcohol (for example in methanol or isopropanol), optionally in the presence of DMF at a temperature comprised between 50 and 100xc2x0 C. for a duration generally comprised between a few hours and overnight. 
Preparation of Intermediates of General Formula (II):
The intermediates of general formula (II) can be prepared by different processes depending on the chemical functions which are set up: amines, carboxamides, ureas, thioureas, sulphonamides, aminosulphonylureas, sulphamides, carbamates, ethers, esters, thioethers, acylureas, etc.:
When:
X=linear or branched alkylene radical having from 1 to 6 carbon atoms
and Y=piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine, 4-aminopiperidine, xe2x80x94NR3xe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94NR3xe2x80x94NHxe2x80x94COxe2x80x94Z2xe2x80x94, xe2x80x94NHxe2x80x94NHxe2x80x94Z2xe2x80x94, xe2x80x94NR3xe2x80x94Oxe2x80x94Z2xe2x80x94
The amines of general formula (II), diagram 2, in which A, X, Y and R6 are as defined above, can be obtained by nucleophile substitution of the halogenated derivatives of general formula (VI) by an amine of general formula (VII). The reaction is carried out, for example, in DMF in the presence of K2CO3 at 20xc2x0 C. The halogenated derivatives of general formula (VI) can be accessed, for example, by bromation of the primary alcohols of general formula (V) using PBr3, at 0xc2x0 C., in anhydrous THF. The alcohols of general formula (V) which are not commercially available can be prepared according to methods described in the literature (Tetrahedron Lett. (1983), 24, (24), 2495-2496). 
The amines of general formula (VII) in which Y represents homopiperazine, 2,5-dimethylpiperazine, 4-aminopiperidine or more generally xe2x80x94NR3xe2x80x94Z2xe2x80x94NR3xe2x80x94 are synthesized in three stages from the corresponding commercial diamines. The diamines are selectively mono-protected in the form of the carbamate (Synthesis (1984), (12), 1032-1033; Synth. Commun. (1990), 20, (16), 2559-2564) before reaction by nucleophile substitution on a fluoronitrobenzene, in particular 4-fluoronitrobenzene. The amines, previously protected, are released at the last stage, according to methods described in the literature (T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Second Edition (Wiley-Interscience, 1991)), in order to produce intermediates of general formula (VII).
When:
X=xe2x80x94Z1xe2x80x94COxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94COxe2x80x94
and Y=piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine, 4-aminopiperidine, xe2x80x94NR3xe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94NR3xe2x80x94NHxe2x80x94COxe2x80x94Z2xe2x80x94, xe2x80x94NHxe2x80x94NHxe2x80x94Z2xe2x80x94, xe2x80x94NR3xe2x80x94Oxe2x80x94Z2xe2x80x94
The carboxamides of general formula (II), diagram 3, in which A, X, Y and R6 are as defined above, are prepared by condensation of the commercial carboxylic acids of general formula (VIII) for X=xe2x80x94Z1COxe2x80x94 and of general formula (IX) for X=xe2x80x94CHxe2x95x90CHxe2x80x94COxe2x80x94 with amines of general formula (VII). The non commercial acids can be synthesized according to methods similar to those described in the literature (J. Org. Chem. (1974), 39 (2), 219-222; J. Amer. Chem. Soc. (1957), 79, 5019-5023, and CHIMIA (1991), 45 (4), 121-123 when A represents a 6-alkoxy-2,5,7,8-tetramethylchromane radical). The amines of general formula (VII) in which Y represents homopiperazine, 2,5-dimethylpiperazine, 4-aminopiperidine, or more generally xe2x80x94NR3xe2x80x94Z2xe2x80x94NR3xe2x80x94 are prepared according to methods similar to those described in the previous paragraph. The carboxamide bonds are formed under standard conditions for peptide synthesis (M. Bodanszky and A. Bodanszky, The Practice of Peptide Synthesis, 145 (Springer-Verlag, 1984)) in THF, dichloromethane or DMF in the presence of a coupling reagent such as dicyclohexylcarbodiimide (DCC), 1.1xe2x80x2-carbonyldiimidazole (CDI) (J. Med. Chem. (1992), 35 (23), 4464-4472) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC or WSCI) (John Jones, The chemical synthesis of peptides, 54 (Clarendon Press, Oxford, 1991)). 
When:
X=xe2x80x94Z1xe2x80x94NR3xe2x80x94COxe2x80x94
and Y=xe2x80x94Z2xe2x80x94Qxe2x80x94
The carboxamides of general formula (II) in which A, X, Y and R6 are as defined above can also be prepared, as in diagram 4, by peptide condensation of an amine of general formula (X) with a commercial acid of general formula (XI). When X=xe2x80x94NR3xe2x80x94COxe2x80x94 and R3=H, the compounds of general formula (X) are anilines which are obtained by hydrogenation, in the presence of a catalytic quantity of Pd/C, the corresponding nitrobenzene derivatives, themselves synthesized according to a method described in the literature (J. Org. Chem. (1968), 33 (1), 223-226). When X-xe2x80x94NR3xe2x80x94COxe2x80x94 and R3 is a linear or branched alkyl radical having from 1 to 6 carbon atoms, the monoalkylamines can be obtained according to a process described in the literature (U.S. Pat. Nos. 3,208,859 and 2,962,531). The non-commercial carboxylic acids of general formula (XI) can be accessed using methods described in the literature (Acta Chem. Scand. (1983), 37, 911-916; Synth. Commun. (1986), 16 (4), 479-483; Phophorus, Sulphur Silicon Relat. Elem. (1991), 62, 269-273). 
When:
X=xe2x80x94Z1xe2x80x94NR3xe2x80x94COxe2x80x94
and Y=xe2x80x94NHxe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94NHxe2x80x94COxe2x80x94Z2xe2x80x94Qxe2x80x94 with Q=Oxe2x80x94Z3xe2x80x94, R3xe2x80x94Nxe2x80x94Z3xe2x80x94 or Sxe2x80x94Z3xe2x80x94,
The ureas of general formula (II), diagram 5, in which A, X, Y and R6 are as defined above, are prepared by the addition of an amine of general formula (X) on an isocyanate of general formula (XII), (XIII) or (XIV) in a solvent such as chloroform at 20xc2x0 C. Synthesis of non-commercial isocyanates of general formula (XII) is described in the literature (J. Med. Chem. (1992), 35 (21), 3745-3754). The halogenated intermediate ureas (XV) and (XVII) are then substituted by a derivative of general formula (XVI), in which Q represents Oxe2x80x94Z3xe2x80x94, R3xe2x80x94Nxe2x80x94Z3xe2x80x94 or Sxe2x80x94Z3xe2x80x94, in the presence of a base such as, for example, K2CO3 or NaH in an aprotic solvent such as THF or DMF in order to finally obtain ureas of general formula (II). 
When:
X=xe2x80x94Z1xe2x80x94NHxe2x80x94COxe2x80x94
and Y=piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine, 4-aminopiperidine, xe2x80x94NR3xe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94NR3xe2x80x94NHxe2x80x94COxe2x80x94Z2xe2x80x94, xe2x80x94NHxe2x80x94NHxe2x80x94Z2xe2x80x94, xe2x80x94NR3xe2x80x94Oxe2x80x94Z2xe2x80x94
The ureas of general formula (II), diagram 6, in which A, X, Y and R6 are as defined above, are prepared by the addition of an amine of general formula (VII), described previously, onto an isocyanate of general formula (XVIII) in the presence of a base such as diisopropylethylamine.
The isocyanates of general formula (XVIII) are synthesized from primary amines of general formula (X), described previously, triphosgene and a tertiary amine (J. Org. Chem. (1994), 59 (7), 1937-1938).
The amines of general formula (VII) in which Y-xe2x80x94NHxe2x80x94Oxe2x80x94 are prepared according to a method described in the literature (J. Org. Chem. (1984), 49 (8), 1348-1352). 
When:
X=xe2x80x94Z1xe2x80x94NR3xe2x80x94COxe2x80x94
and Y=xe2x80x94NR3xe2x80x94SO2xe2x80x94NR3xe2x80x94Z2xe2x80x94
The aminosulphonylureas of general formula (II), diagram 7, in which A, X, Y and R6 are as defined above, are prepared by the addition of amines of general formula (X), described previously, onto chlorosulphonylisocyanate (J. Med. Chem. (1996), 39 (6), 1243-1252). The intermediate chlorosulphonylurea (XIX) is then condensed on the amines of general formula (VII), described previously, in order to produce the aminosulphonylureas of general formula (II) which can optionally be alkylated by a halogenated derivative in the presence of a base such as, for example, NaH in order to produce derivatives of general formula (II). 
When:
X=xe2x80x94Z1xe2x80x94NR3xe2x80x94SO2xe2x80x94
and Y=xe2x80x94Z2xe2x80x94Qxe2x80x94, with Q=Oxe2x80x94Z3xe2x80x94, R3xe2x80x94Nxe2x80x94Z3xe2x80x94 or Sxe2x80x94Z3xe2x80x94,
The sulphonamides of general formula (II), diagram 8, in which A, X, Y and R6 are as defined above, are prepared by the addition of amines of general formula (X), described previously, onto halogenoalkylsulphonyl chlorides of general formula (XX). The halogenoalkylsulphonamides of general formula (XXI), obtained intermediately, are then condensed on an alcohol, an amine or a thiol of general formula (XVI) in the presence of a base such as, for example, K2CO3 or NaH, in a polar solvent such as, for example, acetonitrile or DMF. 
When:
X=xe2x80x94Z1xe2x80x94NR3xe2x80x94SO2xe2x80x94
and Y=xe2x80x94NR3xe2x80x94Z2xe2x80x94Qxe2x80x94
The sulphamides of general formula (II), diagram 9, in which A, X, Y and R6 are as defined above are prepared in three stages from amines of general formula (X) and chlorosulphonylisocyanate. The reaction of an alcohol, such as tBuOH, on the isocyanate function of chlorosulphonylisocyanate (Tetrahedron Lett. (1991), 32 (45), 6545-6546) leads to an intermediate of chlorosulphonylcarbamate type, which reacts in the presence of an amine of general formula (X) to produce a derivative of carboxylsulphamide type of general formula (XXII). The treatment of this intermediate in a strong acid medium produces the sulphamide derivative of general formula (XXIII). Alkylation of the compounds of general formula (XXIII) by the halogenated derivatives of general formula (XXIV) in the presence of a base such as, for example, NaH in a polar aprotic solvent allows sulphamide derivatives of general formula (II) to be obtained. 
When:
X=xe2x80x94Z1xe2x80x94NR3xe2x80x94COxe2x80x94and Y=xe2x80x94Oxe2x80x94Z2xe2x80x94Qxe2x80x94
The carbamates of general formula (II), diagram 10, in which A, X, Y and R6 are as defined above, are prepared by the reaction of amines of general formula (X), described previously, with chloroformate derivatives of general formula (XXV) prepared according to a method described in the literature (Tetrahedron Lett. (1993), 34 (44), 7129-7132). 
When: X=xe2x80x94Z1xe2x80x94COxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94COxe2x80x94
and Y=xe2x80x94Oxe2x80x94Z2xe2x80x94Qxe2x80x94
The esters of general formula (II), diagram 11, in which A, X, Y and R6 are as defined above, are prepared by the reaction of acids of general formula (VIII) or (IX) and alcohols of general formula (XXVI) in the presence de dicyclohexylcarbodiimide and of a catalytic quantity of 4-dimethylaminopyridine in a solvent such as, for example, THF or DMF at 20xc2x0 C. 
When:
X=xe2x80x94Z1xe2x80x94
and Y=xe2x80x94Oxe2x80x94COxe2x80x94Z2xe2x80x94Qxe2x80x94
The esters of general formula (II), diagram 12, in which A, X, Y and R6 are as defined above, can also be prepared by the reaction of acids of general formula (XI), described previously, with the alcohols of general formula (V) under the conditions described previously. 
When:
X=xe2x80x94Z1xe2x80x94NR3xe2x80x94CSxe2x80x94
and Y=xe2x80x94NHxe2x80x94Z2xe2x80x94Qxe2x80x94, piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine, 4-aminopiperidine, xe2x80x94NR3xe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94NHxe2x80x94NHxe2x80x94Z2xe2x80x94, xe2x80x94NR3xe2x80x94Oxe2x80x94Z2xe2x80x94
The thioureas of general formula (II) in which A, X, Y and R6 are as defined above, are prepared from the ureas described previously using Lawesson""s reagent, following an experimental protocol described in the literature (J. Med. Chem. (1995), 38 (18), 3558-3565).
When:
X represents a bond
Y=xe2x80x94Oxe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94Sxe2x80x94Z2xe2x80x94Qxe2x80x94
and Q=xe2x80x94HNxe2x80x94
The etheroxides or thioetheroxides of general formula (II), diagram 13, in which A, X, Y and R6 are as defined above are prepared from dihydroquinones of general formula (XXVII) (J. Chem. Soc., Perkin Trans. I, (1981), 303-306) or thiophenols of general formula (XXVIII) (Bio. Med. Chem. Letters, (1993), 3 (12), 2827-2830) and an electrophile (E+) such as, for example, bromoacetonitrile or 4-nitrophenyloxazolinone, in the presence of K2CO3 (J. Heterocyclic Chem., (1994), 31, 1439-1443). The nitrites must be reduced (lithium hydride or catalytic hydrogenation) in order to produce intermediates of general formula (XXIX) or (XXX). The opening of the nitrophenyloxazolinones, accessible by reaction of the corresponding nitroanilines with chloroethylchloroformate as described in the literature (J. Am. Chem. Soc., (1953), 75, 4596), by phenols or thiophenols leads directly to compounds of general formula (XXIX) or (XXX) which are then condensed on fluoronitrobenzene in order to produce intermediates of general formula (II). 
When:
X represents xe2x80x94Z1xe2x80x94COxe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94COxe2x80x94
Y=xe2x80x94NR3xe2x80x94COxe2x80x94Qxe2x80x94
and Q=R3xe2x80x94Nxe2x80x94Z3 
The acylureas of general formula (II), diagram 14, in which A, X, Y and R6 are as defined above are prepared by condensation of acids of general formula (VIII) or (IX), diagram 3, and ureas of general formula (XXXI) in the presence of a coupling agent usually used in peptide synthesis, as described previously, in a solvent such as, for example, dichloromethane or DMF. The ureas of general formula (XXXI) are accessible from isocyanates of general formula (XII), diagram 5, according to a method in the literature (J. Chem. Soc., Perkin Trans. 1, (1985), (1), 75-79). 
Unless they are defined differently, all the technical and scientific terms used here have the same meaning as that usually understood by an ordinary specialist in the field to which the invention belongs. Similarly, all publications, Patent Applications, Patents and other references mentioned here are incorporated by way of reference.